Breast cancer is the most common cancer among women excluding skin cancers. Considerable evidence associated DNA damage/repair with breast cancer risk; however, conducting a large population screening for every cancer susceptibility gene (e.g., DNA repair) is not yet feasible, and it is still not clear to what extent DNA repair genetic variants contribute to repair function and breast cancer risk. To provide more effective etiology-based strategies for cancer prevention, our long-term objectives are: (i) to evaluate the genetic regulation of DNA damage/repair in breast cancer susceptibility; (ii) to identify high-risk populations by using validated DNA damage/repair markers; and (iii) to reduce breast cancer risk in genetically susceptible (sub)populations through effective intervention. To achieve our long-term goals, the proposed study's primary objective is to test the working hypothesis that amino acid substitution variants of DNA repair genes impede repair function, elevate DNA damage, and increase risk of breast cancer. Since multiple DNA repair pathways are required to maintain genome integrity, and many genes are involved in different repair pathways, genetic defects in multiple DNA repair genes may have additive or multiplicative effects on repair functions and human breast cancer risk. Therefore, genotypes and phenotypes in different repair pathways must be evaluated simultaneously in order to fully assess their impact on breast cancer susceptibility. Our secondary objective is to test whether concurrent germ line single nucleotide polymorphisms (SNPs) in base excision repair (BER), nucleotide excision repair (NER), and double-strand break/recombination repair (DSB/RR) have additive or multiplicative effects on breast cancer risk. We propose to expand our parent breast cancer case-control study to 800 cases and 800 controls (frequency-matched to cases by race and age [+/- 5 yrs]) in order to assess gene-gene interactions in breast cancer risk. A baseline questionnaire will collect information on established breast cancer risk factors. Genomic DNA will be used for genotyping assays. Peripheral lymphocytes will be used for four DNA damage/repair functional assays. The multidisciplinary research team is already in place for the research. We believe this proposed research will advance our knowledge of genetic susceptibility to breast cancer and targets for prevention. This information can be translated into health behavior promotion because genetically susceptible (sub)populations are more motivated for screening and intervention.